Positron emission tomography imaging of poststroke angiogenesis.
OBJECTIVE
Vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFRs) play important roles during neurovascular repair after stroke. In this study, we imaged VEGFR expression with positron emission tomography (PET) to noninvasively analyze poststroke angiogenesis.


METHODS
Female Sprague-Dawley rats after distal middle cerebral artery occlusion surgery were subjected to weekly MRI, (18)F-FDG PET, and (64)Cu-DOTA-VEGF(121) PET scans. Several control experiments were performed to confirm the VEGFR specificity of (64)Cu-DOTA-VEGF(121) uptake in the stroke border zone. VEGFR, BrdU, lectin staining, and (125)I-VEGF(165) autoradiography on stroke brain tissue slices were performed to validate the in vivo findings.


RESULTS
T2-weighed MRI correlated with the "cold spot" on (18)F-FDG PET for rats undergoing distal middle cerebral artery occlusion surgery. The (64)Cu-DOTA-VEGF(121) uptake in the stroke border zone peaked at approximately 10 days after surgery, indicating neovascularization as confirmed by histology (VEGFR-2, BrdU, and lectin staining). VEGFR specificity of (64)Cu-DOTA-VEGF(121) uptake was confirmed by significantly lower uptake of (64)Cu-DOTA-VEGF(mutant) in vivo and intense (125)I-VEGF(165) uptake ex vivo in the stroke border zone. No appreciable uptake of (64)Cu-DOTA-VEGF(121) was observed in the brain of sham-operated rats.


CONCLUSIONS
For the first time to our knowledge, we successfully evaluated the VEGFR expression kinetics noninvasively in a rat stroke model. In vivo imaging of VEGFR expression could become a significant clinical tool to plan and monitor therapies aimed at improving poststroke angiogenesis.
Cai
Weibo
W
The Molecular Imaging Program at Stanford, Department of Radiology, Stanford University, Stanford, CA, USA.
Guzman
Raphael
R
Hsu
Andrew R
AR
Wang
Hui
H
Chen
Kai
K
Sun
Guohua
G
Gera
Atul
A
Choi
Raymond
R
Bliss
Tonya
T
He
Lina
L
Li
Zi-Bo
ZB
Maag
Anne-Lise D
AL
Hori
Nobutaka
N
Zhao
Heng
H
Moseley
Michael
M
Steinberg
Gary K
GK
Chen
Xiaoyuan
X
D000818:Animals; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D001973:Bromodeoxyuridine; D049109:Cell Proliferation; D002536:Cerebral Arteries / Q000000981:diagnostic imaging* / Q000378:metabolism; D003301:Copper Radioisotopes; D004195:Disease Models, Animal; D005260:Female; D019788:Fluorodeoxyglucose F18; D020244:Infarction, Middle Cerebral Artery / Q000000981:diagnostic imaging* / Q000503:physiopathology; D007700:Kinetics; D008279:Magnetic Resonance Imaging; D018919:Neovascularization, Physiologic / Q000502:physiology*; D049268:Positron-Emission Tomography / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley; D040262:Receptors, Vascular Endothelial Growth Factor / Q000032:analysis* / Q000378:metabolism; D020127:Recovery of Function / Q000502:physiology; D020521:Stroke / Q000000981:diagnostic imaging* / Q000503:physiopathology; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000378:metabolism
D015415:Biomarkers; D003301:Copper Radioisotopes; D042461:Vascular Endothelial Growth Factor A; D019788:Fluorodeoxyglucose F18; D040262:Receptors, Vascular Endothelial Growth Factor; D001973:Bromodeoxyuridine